1. Field of the Invention
This invention relates generally to the field of steroids, and in particular, to new 11.beta.-substituted 19-norprogesterone analogs which possess antiprogestational or progestational activity.
2. Discussion of the Background
There have been many prior attempts over the past few decades to prepare steroids with antihormonal activity. These have been reasonably successful where anti-estrogens and anti-androgens are concerned. The discovery of effective antiprogestational and antiglucocorticoid steroids, however, has proved to be a formidable task for the steroid chemist. It has been generally recognized for some years, however, that antiprogestational steroids would find wide applicability in population control, while antiglucocorticoids would be extremely valuable in the treatment of, for example, Cushing's syndrome and other conditions characterized by excessive endogenous production of cortisone. In the last decade largely through the efforts of Teutsch et al of the Roussel-Uclaf group in France, a new series of 19-nortestosterone derivatives has been synthesized with strong affinity for the progesterone and glucocorticoid receptors and with marked antiprogestational and antiglucocorticoid activity in vivo. This important discovery revealed the existence of a pocket in the progesterone/cortisone receptors able to accommodate a large 11.beta.-substituent on selected 19-nortestosterone derivatives. By suitable selection of such a substituent steroids with antihormonal properties were obtained.
The pioneering studies of Teutsch et al on the synthesis of antiprogestational and antiglucocorticoid steroids is summarized in a recent review (G. Teutsch in Adrenal Steroid Antagonism. Ed. M. K. Agarwal, Walter de Gruyter and Co., Berlin, 1984. pp. 43-75) describing work leading to the discovery of RU-38,486 (I), the first steroid of this type selected for clinical development. See FIG. 1. RU-38,486 or mefipristone was found to be an effective antiprogestational/contragestative agent when administered during the early stages of pregnancy (IPPF Medical Bulletin 20; No. 5, 1986). In addition to these antiprogestational properties, mefipristone had very significant antiglucocorticoid activity and was successfully used by Nieman et al (J. Clin. Endocrinology Metab. 61:536, 1985) in the treatment of Cushing's syndrome. In common with the vast majority of steroidal hormone analogs, mefipristone additionally exhibits a range of biological properties. Thus, for example, it exhibits growth-inhibitory properties towards estrogen-insensitive T47Dco human breast cancer cells (Horwitz, Endocrinology 116:2236, 1985). Experimental evidence suggests that the metabolic products derived from mefipristone contribute to its antiprogestational and antiglucocorticoid properties (Heikinheimo et al, J. Steroid Biochem. 26:279, 1987).
There have been a number of attempts by various workers to modify the mefipristone structure in order to obtain separation of the antiprogestational activity from the antiglucocorticoid activity. Thus, the Schering group (Steroids 44:349-519, 1984) has described analogs of mefipristone termed ZK 98.299 (II) and ZK 98.734 (III). See FIG. 1. Mefipristone is the most active antiglucocorticoid steroid relative to its antigestagenic potency while steroid (III) is the least active. Steroid (II) has an intermediate position in this respect.
Comparison of the contragestative properties of these three antiprogestational steroids (Elger et al., J. Steroid Biochem. 25:835, 1986) has not only revealed different endocrinological profiles, but has indicated the critical importance of the ratio of antiglucocorticoid to antiprogestational activity to the biological activity. It thus seems inevitable that a series of related structures possessing a gradation of antiprogestational/antiglucocorticoid properties will need to be developed in order to provide contragestative/antiglucocorticoid/antitumor products designed for specific clinical situations. Unfortunately, the art has not yet reached the stage when accurate predictions of biological properties on the basis of chemical structures can be made so that a degree of empiricism is unavoidable.
There continues to be a need for the development of new steroids with varying degrees of antiprogestational and antiglucocorticoid activities.